Naturally occurring prostaglandins and certain derivatives thereof have been suggested for therapeutic use for the management of cardiovascular, gastro-intestinal, renal, pulmonary, dermatologic, ocular, genital and reproductive conditions. However, because of the side effects of natural prostaglandins and also of their more selective currently available derivatives or analogues, most of the therapeutic potential of such compounds has not yet been realized. This is quite evident from the fact that only a very limited number of prostaglandin-based pharmaceuticals have been made available to the market, in spite of the extensive literature and number of patents and patent applications suggesting their use.
Prostaglandins are a group of naturally occurring compounds derived from unsaturated 20-carbon fatty acids. Virtually all tissues of the body produce prostaglandins and other eicosanoids. The prostaglandins have a variety of important physiologic functions and are classified as autacoids or "local hormones".
The basic chemical structure of naturally occurring prostaglandins is illustrated below: ##STR2## Prostaglandins generally consist of a cyclopentane ring, denoted "X" in the above formula, and two side chains. The upper side chain or "alpha chain" contains 7 carbon atoms. The lower side chain or "omega chain" contains 8 carbon atoms. The end of the alpha chain is normally a carboxylic acid moiety, as indicated above. The side chains may contain 1 to 3 double bonds, most frequently 2, the double bonds being situated between carbon atoms 5 and 6 on the alpha chain and between atoms 13 and 14 on the omega chain. The double bond on the alpha chain exhibits cis-configuration, whereas the double bond on the omega chain exhibits trans-configuration. A substituent group on carbon 15 in the omega chain is preferred for maximal biological activity. In naturally occurring prostaglandins this substituent is hydroxyl, as indicated above. The configuration and functionalities of the cyclopentane ring (X) is important for selectivity to different prostaglandin receptors and the various configurations are those depicted below: ##STR3##
Different classes of prostaglandins are identified by suffixes A, B, C, D, E, P or J depending on the functionalities of the five membered ring, that is the configuration and substituents of the cyclopentane ring. Prostaglandins A, B and C probably are not naturally occurring but rather artificial prostaglandins. Nevertheless they exert considerable biologic activity.
In order to enhance delivery and to improve chemical stability of prostaglandins the carboxylic acid moiety on the alpha chain can be esterified, for instance with hydrocarbon groups containing 1-10 carbon atoms, especially 1-6 carbons, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl or benzyl. Such esterified prodrugs of prostaglandins have been described in several patents and patent applications related to ophthalmic use (see for example, U.S. Pat. No. 4,599,353, U.S. Pat. No. 5,296,504 and W092/02496). Depending on the specific prostaglandin analogue, other derivatives with increased hydrophilicity, such as amides and salts, e.g. the sodium salt, may also be employed.
Glutathione-prostaglandin conjugates and related compounds have been reported in the literature relating to the cytotoxicity of PGA and PGD, see e.g. Cagen, Fales and Pisano, J. Biological Chemistry 251, 6550-54 (1976); Cagen and Pisano, Biochimica et Biophysica Acta 573, 547-51 (1979); Honn and Marnett, Biochemical and Biophysical Research Comn. 129, 34-40 (1985); Atsmon et al., Cancer Res. 50, 1879-85 (1990); Parker and Ankel, Biochemical Pharmacology 43, 1053-60 (1992); Ohno, et al., Eicosanoids 5 81-85 (1992). However, the biological effects of these compounds, other than cytotoxicity or the lack thereof, have not been reported.